The pharmaceutical industry has, for a long time, attempted to solve the problem of prolonging the period of effective action of medicaments. This problem is particularly important in the case where the period of effective action is short and also if there is a problem of conditioning two substances, or mixtures of substances, which are incompatible with one another in the same tablet especially when it would be advantageous to administer these substances in association with one another.
It has been proposed to solve both of these problems by producing "multi-layer" tablets in which a plurality of medicamental substances are distributed in different layers, superposed on one another by successive pressings.
The multi-layer tablets which have been produced with the object of constituting controlled-release types of medicament, comprise a plurality of superposed layers, the most common number of layers being three. Each of these layers has such a composition that the medicaments are liberated at intervals of time which are spaced apart. When the multi-layer tablets are intended to separate active constituents which are incompatible with one another, three layers are again usually provided, which comprise a thin central layer of an inert substance which separates two layers of much greater thickness, which contain the incompatible medicaments.
Nevertheless, the multi-layer tablets already known which are of the controlled-release type, that is to say, tablets which release the active ingredients in a controlled manner over a period of time, suffer from the disadvantage that it cannot be ensured that the active constituent is liberated in a programmed manner at sufficiently regular intervals.
It is for this reason that attempts have been made to find other forms which produce a controlled-release effect over a period of time. It is for this reason that microcapsules have been proposed.
The microcapsules comprise elemental particles of small dimensions, that is to say, having dimensions from a few microns to several millimeters. These microcapsules may be in a solid or liquid state and may be coated with a protective covering to form a "micro-package". This "micro-package" is capable of being destroyed by mechanical or any bio-chemical action, at the time when it is desired to use the "micro-packaged" substance. Alternatively, the structure thereof may be such that it constitutes a coating through which the active constituent is progressively liberated.
The protective coating covering the elemental particles is obtained either by chemical or mechanical methods of encapsulation. The coatings of microcapsules, which are intended to act in a controlled-release manner over a period of time, are prepared by methods known per se. In particular, it is possible to regulate the rate of external diffusion of the encapsulated product by different methods. It is particularly possible to vary the thickness, to a greater or lesser extent, of the coating and, above all, by providing the coating with a predetermined micro-porosity.
Nevertheless, these microcapsules are relatively fragile structures. Until now, it has proved impossible to put them into the form of tablets. A tablet is, of course, a very convenient form of administration since it reduces the volume to be swallowed by a patient. In fact, in the course of the process of mixing with pressing with adjuvants or other associated substances, an abrasive effect is noticed. This affects the external layer of the microcapsules and leads to at least a partial destruction of the microcapsule. This, accordingly, affects the quality of the controlled-release effect desired. Moreover, the direct pressing of the microcapsule, irrespective of whether or not the microcapsule is of the double core coating type, has the effect of destroying its external and internal structure and the tablet obtained loses all its effectiveness.
This impossibility of pressing microcapsules under satisfactory conditions whilst preserving the wholeness of the microcapsules, has necessitated the microcapsules to be hitherto used in the form of gelules. This pharmaceutical form whilst it enables the microcapsules to retain their effectiveness, nevertheless suffers from a disadvantage which is of some consequence, that is to say, it is difficult to swallow. Moreover, this format is unsuitable when one attempts to associate microcapsules with one or more other active substances. In fact, not only does this entail extremely large gelules, but additionally, the operation of mixing the microcapsules with other granulated active agents has an abrasive effect due to the contact of the microcapsules with one another. The resultant erosion of the microcapsules has the effect of annoyingly affecting the controlled-release.